Effect of a 5HT3-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome

In some patients with the irritable bowel syndrome, rectal urgency and discomfort are major clinical problems and, under experimental conditions, these symptoms are perceived at lesser volumes of rectal distension than they are in asymptomatic controls. Further, a 5-hydroxytryptamine type-3 receptor antagonist increased the threshold for rectal discomfort in irritable bowel syndrome. Our aims were, (a) to measure rectal sensation during isobaric distensions of the rectum, and (b) to test the effect of another selective 5HT₃ antagonist, ondansetron 0.15 mg/kg, on rectal sensitivity, colonic tone, rectal tone and manometric responses. Ten healthy volunteers and five patients with diarrhoea-predominant irritable bowel syndrome were studied. A multilumen barostatmanometric assembly was placed in the descending colon, and a second barostat balloon was positioned in the rectum. Tone in the wall of the colon and rectum was measured by the barostat balloon volume during a constant pressure clamp, while intraluminal pressures were recorded by manometry; perceived sensations were also recorded before and after the intravenous administration of ondansetron or placebo in blinded fashion. Rectal resistance to stretch was greater and rectal urgency was induced by lower distending pressures in irritable bowel syndrome, however, basal tone in the rectum was similar in health and irritable bowel syndrome. Ondansetron did not change rectal sensitivity (first sensation or urgency) or tone. Rectal distension did not alter tone in the descending colon or colonic manometry; ondansetron did not influence any index of colonic function. We conclude that in diarrhoea-predominant irritable bowel syndrome there is reduced rectal compliance and the rectum is abnormally sensitive to a pressure stimulus, but this is not altered by 5HT₃-blockade with ondansetron at the dose used.     

Comparison of the bioavailability of oral,rectal and intramuscular promethazine

The bioavailabilities of generic and reference promethazine 50 mg rectal suppositories were compared with that of 50 mg reference oral solution (24 subjects), and all three treatments were compared with a 50 mg reference i.m. injection (six subjects). Plasma samples were assayed by an HPLC method with triflupromazine as the internal standard. Both suppositories produced lower peak plasma concentrations (C_max) and longer times to peak concentration (T_max) than did the oral solution. There were no significant differences in the mean area under the plasma concentration–time curves (AUC) from 0 to 24 h among the three treatments. The C_max of the i.m. injection was significantly higher than the other three treatments, while the T_max of the injection was significantly shorter than the reference suppository only. The mean AUC of the injection was significantly greater than the AUCs of the other three treatments. Rectal suppositories of promethazine are more slowly absorbed than oral solutions or i.m. injections; rectal suppositories and oral solutions are less bioavailable than i.m. injections. Diminished systemic bioavailability may result from extensive first-pass hepatic metabolism that occurs after both oral and rectal dosing. There is a high degree of inter-subject variation in the bioavailability of promethazine rectal suppositories and oral solutions.     

Bioavailability of Propranolol After Oral,Sublingual, and Intranasal Administration

The bioavailability of propranolol was compared after oral, sublingual, and intranasal administration in eight healthy male volunteers. Relative to the bioavailability after intranasal (in) administration, which was previously shown to be nearly complete (F _relin = 100%), the sublingual (sl) administration of a standard 10-mg tablet gave a bioavailability of F _relsl = 63 ± 22%, while the oral (or) administration yielded only F _relor = 25 ± 8%. The serum concentration–time curves of propranolol after sublingual administration resembled those of a sustained-release preparation. This sustained-release phenomenon after the sublingual route is reflected in the mean residence times (MRTs) of propranolol in the body (MRT_or = 5.7 ± 1.3 hr, MRT_sl - 6.4 ± 1.3 hr, MRT_in = 4.6 ± 1.0 hr; mean ± SD; N = 8). MRTs after sublingual administration were significantly longer than after the oral and the intranasal doses (P < 0.05 and P < 0.002, respectively).     

In Vitro-In Vivo Evaluation of a Controlled Release Buccal Bioadhesive Device for Oral Drug Delivery

Purpose. To investigate the use of buccal bioadhesive device in targeting controlled drug delivery to the gastrointestinal tract. Methods. A three-leg crossover study was designed to evaluate the application of buccal bioadhesive device for providing controlled drug delivery to the gastrointestinal tract of a model drug cyanocobalamin in four healthy adult male beagle dogs. Results. In vitro dissolution studies using deionized water as the medium indicated that 100% of the drug was released within 15 min from a immediate release oral capsule formulation, whereas 90% of the drug was released within a period of 18 hrs from a buccal bioadhesive device formulation. Drug release from the buccal bioadhesive devices appeared to follow Higuchi's square root of time dependent model. The terminal half-life of the drug following I.V. administration in four dogs was found to be 16.4 ± 2.4 hrs. Following immediate release oral capsule administration of the drug C_max, t_max and bioavailability were 2333 ± 1469 ng/L, 2.5± 1.0 hrs and 14.1 ± 7.9%, respectively. Following buccal bioadhesive device administration of the drug C_max, t_max and bioavailability were 4154 ± 1096 ng/L, 11 ± 1.2 hrs and 35.8 ± 4.1%, respectively. Significantly higher bioavailability of the drug was observed with the buccal bioadhesive device administration when compared to the immediate release oral capsule. Conclusions. The buccal bioadhesive device appears to improve the oral bioavailability of cyanocobalamin by providing controlled delivery of the drug to the gastrointestinal tract.     

Comparison of Zafirlukast (Accolate®) Absorption After Oral and Colonic Administration in Humans

Purpose. This study characterized the gastrointestinal (GI) absorptionof zafirlukast after oral and colonic administration in humans. Methods. Five healthy subjects received zafirlukast solution (40 mg)orally and via an oroenteric tube into the colon in a randomized,crossover fashion. Two additional subjects were dosed into the distalileum. Serial blood samples were obtained and plasma concentrationswere quantitated by HPLC. Results. Mean ± SD pharmacokinetic parameters after oral vs. colonicadministration were: AUC of 2076 ± 548 vs. 602 ± 373 ng*h/mL,respectively, and C_max of 697 ± 314 vs. 194 ± 316 ng/mL, respectively.Mean colon:oral AUC and C_max were 0.29 and 0.30, respectively.Median t_max values were 2.0 and 1.35 hr after oral and colonicadministration. First-order absorption rate constants (K_a and K_ac) wereestimated from a two-compartment model with first-order elimination.K_ac:K_a was <0.5 in 4 of the 5 subjects dosed in the colon. Conclusions. Zafirlukast was absorbed at multiple sites in the GI tract.The rate and extent of zafirlukast absorption was less after colonicthan oral administration. Zafirlukast was significantly absorbed in thedistal ileum. This study demonstrated that gamma scintigraphy, digitalradiography, and fluoroscopy can be used to track the movement andconfirm the location of the oroenteric tube in the GI tract.     

A study to evaluate the effect of ondansetron on psychomotor performance after repeated oral dosing in healthy subjects

The aim of the study was to determine the effect of repeated oral administration of ondansetron, a 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist, on psychomotor performance. The study was of a randomised, double-blind, four-way, cross-over design in 12 healthy subjects, with 1 mg and 8 mg ondansetron, placebo and 2 mg lorazepam evaluated. Each subject received five administrations per treatment period. Ondansetron, 1 mg and 8 mg, and placebo were given as twice daily dosing for 2 1/2 days. Lorazepam was administered as a 2 mg single oral dose which was taken as the fifth administration; placebo was given for the remaining four doses. Within each treatment period, subjects underwent a baseline (pre-dose) assessment of psychomotor performance using four commonly used and validated psychomotor tests, and were then re-assessed after the fifth and final dose over a 7-h, post-dose period. Following dosing with lorazepam, statistically significant changes were seen in five of the six test variables compared with placebo. Ondansetron, at both the 1 mg and the 8 mg doses, did not produce a statistically significant effect on any measure of psychomotor performance compared with placebo.     

Pharmacokinetics of acrivastine after oral and colonic administration

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.     

Absorption of 2′, 3′-Dideoxyinosine from Lower Gastrointestinal Tract in Rats and Kinetic Evidence of Different Absorption Rates in Colon and Rectum

This study explored the rectal route of administration for 2,3-dideoxyinosine (ddI). Rats were given a rectal infusion of nonradiolabeled ddI (200 mg/kg in 0.7 mL saline) over 35 min along with an intravenous (iv) bolus injection of [8-³H]ddI (20 µCi, equivalent to 2.1 µg), which was used to calculate the absolute rectal bioavailability of ddI. Maximal plasma concentrations of rectally administered unlabeled ddI were 5.4 ± 2.2 µg/mL and were reached at the end of the infusion. The rectal bioavailability averaged 15.6 ± 4.4% (n = 9). The second aim of this study was to examine the kinetics of ddI absorption from the colorectal region. Analyses of the absorption rate–time profiles by the Loo–Riegelman and deconvolution methods showed biphasic absorption: a rapid phase during infusion and a slow phase postinfusion. These profiles were inconsistent with a mammillary model with absorption from a single site with one apparent rate constant. The model which gave the best fit for infusion and postinfusion data consisted of two different sites (colon and rectum) with different apparent absorption rate constants. The two sites were connected by a first-order transfer of drug solution from rectum to colon. The apparent absorption rate constant in the rectum was 39-fold higher than that in the colon. In conclusion, these results show absorption of ddI from the colorectal region and suggest the rectal route as an alternative to the oral route. The data further suggest different absorption sites in the colorectal region, with a more rapid absorption in the rectum than in the colon.     

Oral absorption of CGS-20625, an insoluble drug,in dogs and man

Oral bioavailability of highly water-insoluble drugs is often quite limited and variable, requiring the development of improved formulations. Animal models are an essential aspect of the design and testing of such formulations designed to improve absorption in man. The present report compares the absorption of CGS-20625, an insoluble drug, in dog and man after oral administration of the drug as a powder, a solid dispersion capsule, and after gastric and duodenal administration in PEG 400 solution. CGS-20625 powder (20 mg) given orally exhibited slow, delayed absorption in both dog and man, with aC _max of 0.26±0.07 μg/ml atT _max of 3 hr in dog, and 0.01±0.004 μg/ml at 2 hr in man. Administration of CGS-20625 in PEG 400 solution improved absorption in dog and man, with aC _max of 1.2±0.10 μg/ml atT _max of 0.25 hr in dog, and aC _max of 0.10±0.04 μg/ml at 0.5 hr in man.T _max after administration of the hard gelatin capsule formulation was 0.9 and 1.0 hr in dog and man, withC _max of 0.89±0.16 and 0.052±0.014 μg/ml, respectively. Absolute bioavailability of CGS-20625 powder in the dog was 0.67±0.21, whereas the bioavailabilities of the powder and the capsule relative to the PEG 400 solution were 0.84 and 1.1, respectively, in dog, and 0.41 and 0.85 respectively, in man. No significant benefits of duodenal administration were observed. Plasma levels were approximately 10-fold greater and oral clearance was approximately 5-fold less in the dog than in man. Furthermore, pharmacokinetic data were less variable and relative bioavailability was greater in dogs than in humans. Physiological factors in the gastrointestinal tract or greater first-pass metabolism in man may account for these species differences. The relative rate and extent of CGS-20625 absorption were similar between dog and man, in the order of powder <capsule<PEG 400 solution. In addition,in vivo absorption rates in both species reflectin vitro dissolution differences between the powder and the capsule. These data strongly support the use of the dog as a model for developing improved formulations of CGS-20625. Further investigation of the dog as a model to evaluate insoluble drug absorption is warranted.     

Pharmacokinetics of a Single Intravenous and Oral Dose of Pafenolol—a Beta1Adrenoceptor Antagonist with Atypical Absorption and Disposition Properties—in Man

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 µCi [³H]pafenolol. The plasma concentration–time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 ± 0.2 and 3.7 ± 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 ± 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t _1/2l was 6.6 ± 1.8 min. The volumes of distribution were V _c = 0.22 ± 0.08 liter/kg, V _ss = 0.94 ± 0.17 liter/kg, and V _z = 1.1 ± 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 ± 5.1% of the given dose and in the feces to 23.8 ± 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 ± 5.9 and 67.0 ± 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 ± 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 ± 31, 31 ± 15, and 95 ± 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 ± 0.3 hr for the iv dose and 6.7 ± 0.7 hr for the oral dose.     

Pharmacokinetic Study of Zeolite A,Sodium Aluminosilicate,Magnesium Silicate,and Aluminum Hydroxide in Dogs

Zeolite A is a synthetic zeolite which may have therapeutic utility in osteoporotic individuals because of its ability to stimulate bone formation. A study of Zeolite A (30 mg/kg), sodium aluminosilicate (16 mg/kg), magnesium trisilicate (20 mg/kg), and aluminum hydroxide (675 mg) was designed in beagle dogs. The purpose of this study was to compare the oral bioavailability of silicon and aluminum from Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide in dogs. Twelve female dogs received each compound as a single dose separated by one week in a randomized, 4-way, crossover design. Plasma samples were drawn at time 0 and for 24 hours after dosing. The concentrations of silicon and aluminum were determined by graphite furnace atomic absorption. The mean plasma silicon AUC values (±S.D.) were 9.5 ± 4.5, 7.7 ± 1.6, 8.8 ± 3.0, 6.1 ± 1.9 mg · hr/L and the mean plasma silicon C_max values (±S.D.) were 1.07 ± 1.06, 0.67 ± 0.27, 0.75 ± 0.31, 0.44 ± 0.17 mg/L for Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide respectively. Although mean silicon AUC and C_max values were elevated when compared to baseline after administration of the silicon containing compounds, only the AUC from Zeolite A reached statistical significance (p = 0.041). The mean plasma silicon T_maxvalues (±S.D.) were 7.9 ± 6.4, 5.8 ± 4.6, 6.9 ± 6.3 and 8.5 ± 3.4 hrs for Zeolite A, sodium aluminosilicate, magnesium trisilicate and aluminum hydroxide respectively. These values were not statistically different. The mean plasma aluminum AUC values for Zeolite A, sodium aluminosilicate, magnesium trisilicate and aluminum hydroxide (±S.D.) were 342 ± 111, 338 ± 167, 315 ± 69, 355 ± 150 µg · hr/L and the mean aluminum C_max values (±S.D.) were 29 ± 9, 27 ± 14, 24 ± 5 µg/L, 29 ± 11 respectively. The plasma aluminum T_max values (±S.D.) were 3.5 ± 4.1, 4.2 ± 4.3, 5.7 ± 7.3 and 5.0 ± 4.7 hrs for Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide respectively. There was no statistically significant absorption of aluminum from the aluminum containing treatments.     

Effect of an Acute Dose of Alcohol on the Pharmacokinetics of Oral Nifedipine in Humans

Pharmacokinetic and pharmacodynamic interactions of alcohol and nifedipine were assessed in 10 healthy human volunteers. Doses of 20 mg (2 × 10-mg capsules) of nifedipine were administered with either 150 ml of orange juice or 75 ml of alcohol (94%) in 75 ml of orange juice according to a crossover randomized design. Plasma nifedipine levels were monitored for 16 hr after each dosing, along with pulse rate and blood pressure. The relative bioavailability of nifedipine, measured as AUC, was increased by 54% (533 vs 346 ng · hr/ml) after the dose of alcohol (P < 0.0002). However, there were no significant differences between treatments in C _max,t _max, or t _1/2. Although there was no difference in the systolic and diastolic blood pressure and pulse rate between the two treatment groups, the time to reach peak heart rate was significantly faster in the group treated with alcohol (1.4 vs 2.2 hr). This study shows that ethanol increases the bioavailability of nifedipine and decreases the time for onset of increased heart rate.     

Encapsulation of poorly soluble basic drugs into enteric microparticles: a novel approach to enhance their oral bioavailability

Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4 ± 6.8 μm and a span of 1.2 ± 0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder suspension, although C_max and T_max were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability.     

Relative Bioavailability of Ondansetron 8-mg Oral Tablets versus Two Extemporaneous 16-mg Suppositories: Formulation and Gender Differences

Study Objective . To compare the relative bioavailability of two 16-mg extemporaneously prepared suppository formulations with that of an 8-mg commercially available oral tablet. Design . Prospective, crossover bioavailability study. Setting . Inpatient clinical research center. Subjects . Sixteen young, nonsmoking, healthy volunteers. Interventions . Blood samples were obtained 24 and 48 hours after administration of an 8-mg oral ondansetron tablet and 16-mg suppository, respectively. Two 16-mg suppository formulations were compounded using commercially available Fattibase and Polybase. Measurements and Main Results . Ondansetron was well absorbed by both routes of administration. The following pharmacokinetic parameters (mean ± SEM) were obtained for the 8-mg tablet, 16-mg Fattibase suppository, and 16-mg Polybase suppository, respectively: area under the curve (AUC) in men 154.2 ± 21.77, 253.4 ± 72.3, 304.8 ± 62.2 ng·hr/ml; AUC in women 353.6 ± 32.7, 561.6 ± 103.6, and 768.7 ± 117.9 ng·hr/ml; maximum concentration (C_max) in men 45.5 ± 7.0, 40.6 ± 10.4, and 51.2 ± 6.7 ng/ml; C_max in women 51.4 ± 4.8, 47.1 ± 3.9, and 82.9 ± 6.6 ng/ml. Times to C_max (T_max; mean ± SEM) for men were 1.5 ± 0.3, 4.4 ± 0.5, and 2.9 ± 0.3 hours; T_max for women were 1.8 ± 0.3, 4.1 ± 0.4, and 4.4 ± 0.6 hours for the three formulations, respectively. Women had a consistently higher AUC for all three formulations than men (p < 0.05). Conclusion . With the exception of the 16-mg Polybase formulation in women, the two suppositories closely approximated the pharmacokinetics of the 8-mg oral tablet. These results suggest that gender may be a significant factor in ondansetron's disposition.     

Concentration of ondansetron in cerebrospinal fluid following oral dosing in volunteers

This study measured the concentrations of ondansetron in plasma and cerebrospinal fluid (CSF) in six volunteers after oral dosing to steady state. Ondansetron concentrations ranged from 39.5–147 ng ml^–1 in plasma and from 2.6–15.4 ng ml^–1 in CSF. There was good correlation between plasma and CSF concentrations (r=0.89,p=0.017). CSF concentrations were less than 15% of plasma concentrations in all cases, indicating that the rate of penetration of the blood brain barrier by ondansetron is low.     

Absorption kinetics of oral and rectal flecainide in healthy subjects

Summary The absorption kinetics of different pharmaceutical formulations of orally and rectally administered flecainide have been assessed in a cross-over study in 7 healthy volunteers. The subjects received single doses of flecainide after a washout period of at least one week. A tablet, an oral solution, a rectal solution and a 10 min i.v. infusion during 10 min each containing 100 mg flecainide were administered to the subjects in a randomized order.The mean absolute bioavailability was 98%, 78% and 81% for the rectal and oral solutions and the tablet. The lag time after administration of the oral solution was 0.33 h and it was 0.86 h after the tablet and 0.18 h after the rectal solution. The mean time to the peak serum concentration (t_max) after the rectal solution (0.67 h) was shorter than after either the tablet (4 h) or oral solution (1 h). The maximum serum concentration (C_max) was 0.29 mg · 1^–1 after the rectal solution, 0.14 mg · 1^–1 after the tablet and 0.17 mg · 1^–1 after the oral solution. All the volunteers showed significantly higher serum flecainide concentrations during the first 20 min of the absorption phase after rectal administration of 100 mg flecainide as a solution compared to its oral administration.In conclusion: based on the absolute bioavailability, C_max, t_max, and lag times, rectal administration of flecainide solution gave a better absorption profile than after oral tablet or solution.     

Simultaneous Modeling of the Pharmacokinetics and Methemoglobin Pharmacodynamics of an 8-Aminoquinoline Candidate Antimalarial (WR 238605)

Methemoglobin (MHb) formation can be a clinically significant and dose-limiting side effect of 8-aminoquinoline antimalarials. MHb may also protect against cyanide poisoning. A two-compartment pharmacokinetic model, linked to a sigmoid E _max pharmacodynamic model, was developed to predict the MHb levels after administration of 8-[(4-amino-l-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy] quinoline succinate (WR 238605 suc-cinate), a primaquine analogue. Six healthy male beagle dogs received four daily doses of 6.0 mg/kg (base) orally. Forty plasma drug concentrations and 19 MHb levels (effect) were determined over 7 weeks on each dog. Compartmental and noncompartmental pharmacokinetic and parametric and nonparametric pharmacodynamic analyses were performed. Model parameters (mean ± SD) included a V _ss/f of 18.5 ± 2.8 L/kg, CL/f of 83 ± 24 ml/hr/kg, terminal elimination t _1/2 of 169.7 ± 52.0 hr, t _1/2 k _eo of 123.0 ± 22.4 hr, an E _max of 31.3 ± 15.9% MHb, an EC₅₀ of 596 ± 128 ng/ml, and a sigmoidicity coefficient (n) of 1.94 ± 0.47. The model was then validated in three additional dogs given three different dosing regimens. It predicted the peak plasma concentrations and MHb levels and the times of their occurrence well. This model could be useful for dose and sampling time selection in further animal studies and initial human phase I clinical testing.     

Distribution,elimination, metabolism and bioavailability of hexamethylenebisacetamide in rats

Summary Hexamethylenebisacetamide (HMBA), an in vitro differentiating agent, was studied for its pharmaco-dynamic actions in animals. Plasma stability, organ distribution, excretion, oral bioavailability, and estimates of pharmacokinetic parameters and acute lethality were determined in rats. The single dose intraperitoneal LD₅₀ was greater than 3000 mg/kg in both mice and rats. The drug was stable in plasma from several different species during an 8 h in vitro incubation at 37°C. Following a single intravenous (iv) bolus injection (1000 mg/kg) to rats, HMBA was removed from the plasma with a half time of 2.2 ± 0.5 h, and 65 ± 8% of the dose was excreted unchanged in the urine during the first 24 h after dosing. During an 8 h iv infusion, plasma concentrations of 4 mM were easily maintained with no apparent adverse effects. Drug was uniformly distributed, with highest concentrations found in thymus, kidney, liver, and lymph node throughout the first 24 h after a single iv bolus dose. In vivo metabolism was very small, and the presence of apparent metabolites was undetectable until 48 h after iv administration. Oral bioavailability was good (32%), with peak plasma concentrations of 2 mM achieved one hour after oral administration. After oral dosing urinary excretion and plasma decay were comparable to similar data obtained after iv dosing.     

Systemic exposure to rosiglitazone is unaltered by food

Objective: To evaluate the effect of food on the bioavailability and pharmacokinetics of the insulin sensitizer rosiglitazone. Methods: In a randomized, open-label, period-balanced, single-dose, crossover study, rosiglitazone 2 mg was administered to 12 healthy male volunteers either in the fasting state or following a standard high-fat breakfast. The primary end points of the study were AUC_0–inf and C_max. Results: Single oral doses of rosiglitazone were safe and well tolerated. Overall exposure to rosiglitazone was unaffected by food. The geometric mean ratio of AUC_(0–inf) in the fed:fasted regimens was 0.94 (95% CI: 0.82, 1.06); t_1/2 was unaffected. Absorption of rosiglitazone in the fed state was more gradual and sustained than in the fasted state. C_max was reduced by approximately 20% (point estimate 0.80; 95% CI 0.65 to 0.97) and t_max was modestly delayed in the fed state. Conclusion: These data support dosing guidelines that will permit the administration of rosiglitazone without regard to meals for treatment of type 2 diabetes mellitus. Received: 17 July 1998 / Accepted in revised form: 28 October 1998     

Selective reduction in the expression of UGTs and SULTs,a novel mechanism by which piperine enhances the bioavailability of curcumin in rat

Curcumin (CUR) is known to exert numerous health‐promoting effects in pharmacological studies, but its low bioavailability hinders the development of curcumin as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of curcumin, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which piperine enhances the bioavailability of curcumin, the dosage ratio (CUR: PIP) and pre‐treatment with piperine were hypothesized as key factors for improving the bioavailability in this combination. Therefore, combining curcumin with piperine at various dose ratios (1:1 to 100:1) and pre‐dosing with piperine (0.5–8 h prior to curcumin) were designed to investigate their contributions to the pharmacokinetic parameters of curcumin in rats and their effects on the expression of UGT and SULT isoforms. It was shown that the C _max and AUC _0‐t of curcumin were slightly increased by 1.29 and 1.67 fold at a ratio of 20:1, while curcumin exposure was enhanced significantly in all the piperine pre‐treated rats (0.5–8 h), peaking at 6 h (a 6.09‐fold and 5.97‐fold increase in C _max and AUC _0‐t, p  < 0.01), regardless of the unchanged t _1/2 and T _max. Also observed was a time‐dependent inhibition of the hepatic expression of UGT1A6, 1A8, SULT1A1, 1A3, and the colonic expression of UGT1A6 that occurred within 6 h of piperine pre‐treatment but was reversed at 8 h, which correlated with the changes in curcumin exposure. Similarly, the inhibitory effect of piperine on most of the UGTs and SULTs are time‐dependent in Caco‐2 and HepG2 cells. It is concluded that piperine pre‐treatment time‐dependently improves the bioavailability of curcumin through the reversible and selective inhibition of UGTs and SULTs. Copyright © 2016 John Wiley & Sons, Ltd.